Injury to the spinal cord results in paralysis below the level of the injury, and there are no current therapies that are able to restore function. Limited regeneration occurs as result of the local environment, which is deficient in stimulatory factors and has an excess of inhibitory factors. Our long-term goal is to develop multi- functional biomaterials that bridge the injury site to control the microenvironment to promote and direct axonal growth into and through, and to re-enter the host tissue to form functional connections with intact circuitry. In the previous funding periods, we have developed multiple channel bridges that mechanically stabilize the injury that limits secondary damage, and using a transgenic mouse model with a GFP reporter construct expressed predominantly in the corticospinal tract (CST), we demonstrated that large numbers of CST axons grow through the bridge, re-enter the host tissue, and extend up to 3 mm down the cord by 10 weeks post- implantation. Additionally, we have an unparalleled ability to localize delivery of gene therapy vectors, with which expression of neurotrophic factors significantly enhanced the number of regenerating axons. This proposal builds on these results and focuses on enhancing the number of neural progenitors (either through recruitment or transplantation) and promoting their differentiation into mature oligodendrocytes that can myelinate axons and functionally reconnect a significant number of regenerating axons with the intact circuitry below the injury. Our development of bridges is targeted toward the 14% of spinal cord injuries that result from penetrating wounds that create a gap in the spinal cord, and may necessitate a different approach to restoring function than contusion/compression injuries. We propose that providing a bridge soon after a penetrating injury in order to stabilize the spinal cord and attenuate the host response. The bridges could be an off-the- shelf product that is readily available for implantation, and the bridge is initially designed to target survival, migration, and differentiatin of the endogenous progenitor cell population. Alternatively, we investigate delivery of neural stem cells rostral and caudal to the bridge a week or more after the bridge is implanted. While a bridge can be delivered soon after injury, stem cell transplants immediately after injury are contraindicated, as the cells are allogeneic and would require immunosuppression. The survival, recruitment, proliferation, and differentiation of endogenous or exogenous progenitor cells will be targeted through the immune response at the scaffold (Aim 1). We propose to use the bridges to modulate the macrophage phenotype towards M2 in order to promote secretion of pro-regenerative factors following injury. Alternatively, we propose to delivery trophic factors tht target the function of progenitor cells by complementary pathways. The bridge platform can support multiple aspects of the regenerative process, and the well-defined components, which have been used in the clinic, may facilitate the ultimate translation to the clinic.